The Enemy Within: Deleterious Consequences of an Inappropriate Antiviral Response for the Central Nervous System

Background/Purpose: Aicardi-Goutierès syndrome (AGS) is a heterogenous congenital inflammatory disease predominantly affecting the central nervous system mimicking a chronic viral infection. AGS so far has proven refractory to various treatment approaches. In AGS, intracellular nucleic acid accumulation is a key trigger for type I interferon release, similar to that seen in antiviral immunity. Retroelements potentially are a major source of pathogenic nucleic acids; thus, reverse transcriptase inhibitors (RTI) are being evaluated in clinical trials in AGS (https://clinicaltrials.gov/show/NCT02363452).

Methods: We treated three AGS patients with a combination of RTIs on an individual curative trial basis.

Results: Two patients with RNASEH2B mutation and one with SAMHD1 mutation have received RTI treatment for more than 2 years. Clinically, improvement regarding irritability was noted; CSF cell count and protein, neopterin levels, soluble CD25 levels, and IFN α activity improved or normalized. In one patient, symptoms are controlled to a large extent; however, a cerebral vasculitis and glaucoma progressed on continuous treatment. In another case, parental incompliance illustrated the efficacy of antiretroviral therapy. Inconclusive results on repeated interferon signature analyses were a common feature in all our cases.

Conclusion: The rapidly growing understanding of the disease pathomechanisms in AGS may lead to improved treatment strategies. Our preliminary data demonstrate that blocking transcription of endogenous retroelements via RTIs may be a useful tool in the treatment of AGS. However, judging treatment efficacy is extraordinarily challenging in AGS due to the difficulty to separate disease activity from therapeutic effects. Therefore, controlled studies are needed to better define potentially efficacious treatments.